Malignancy following transplantation
Epidemiology

The etiology of post-transplantation malignancy seems to be multifactorial and probably involves a combination of the following events: impaired immune activity against viruses, impaired immunosurveillance of neoplastic cells, DNA damage and disruption of DNA repair mechanisms, and the upregulation of cytokines that can promote tumor progression (for example, transforming growth factor β1, interleukin [IL]-10, and vascular endothelial growth factor).[14] All of these events certainly occur during long-term immunosuppressive therapy after renal transplantation.[14]

Many studies have focused on the relative incidences of malignancies following solid-organ transplantation.[14-19] Solid-organ transplantation has been associated with the following increases in cancer incidence: a 20-fold increase in the incidence of non-melanoma skin cancers, Kaposi's sarcoma, and non-Hodgkin lymphomas; a 15-fold increase in the incidence of renal cell cancer; a fivefold increase in the incidence of melanoma, leukemia, and hepatobiliary, cervical, and vulvovaginal cancers; a threefold increase in the incidence of testicular and bladder cancer; and a twofold increase in the incidence of common tumors such as colon, lung, prostate, stomach, esophagus, pancreas, ovary, and breast tumors.[14]

Immunosuppression during the premalignant phase, however, has been shown to reduce the incidence of breast cancer and prolong life in mice.[20] In addition, one series found that the incidence of breast cancer was 25-30% lower in women who were receiving immunosuppressive therapy after kidney or heart transplantation than it was in the general population.[21] This reduction in the incidence of breast cancer might be the result of immunosuppressive therapies directly inhibiting specific immune mechanisms that can promote the development of breast cancer tumors in some women.[21]

The risk of developing cancer is reported to be 2-4-fold higher among heart transplant recipients than among kidney transplant recipients.[10,22-25] This finding is probably related to the fact that patients who have undergone heart transplantation require higher doses of immunosuppressive agents to prevent rejection. Renal transplant recipients aged <50 years have higher standardized cancer mortality ratios than the general population.[26]
Features

The clinical characteristics of malignancies after renal transplantation are of course related to the origin of the cancer. The time of presentation also depends on the nature of the malignancy, but one study found that the average time to cancer development was approximately 3 years after transplantation.[27] For several common cancers, it seems that solid-organ transplant recipients experience worse outcomes than the general population.[28] In addition, at the time of diagnosis, cancers seem to be more aggressive in solid-organ transplant recipients than in the general population.[28]

Skin cancer
Non-melanoma skin cancers are the most common cancer type following solid-organ transplantation.[17,29] Basal cell carcinomas and squamous cell carcinomas account for >90% of all non-melanoma skin cancers occurring in solid-organ transplant recipients.[17,29] Non-melanoma skin cancers have been reported to occur an average of 8 years after renal transplantation in recipients aged <40 years, and more quickly—after 3 years—in recipients aged >60 years; however, these data might only be a function of the follow-up period of the particular studies.[30,31] In the general population, basal cell carcinoma is more common than squamous cell carcinoma.[32]

Squamous cell carcinoma is the most frequent non-melanoma skin cancer occurring after solid-organ transplantation, with the risk being 100 times greater in transplant recipients than in the general population; the incidence of basal cell carcinoma is 10-fold higher in transplant recipients than in the general population.[29] Both tumor types are generally more aggressive in transplant recipients than in the general population, and the risk of recurrence after treatment is generally higher.[29] Lesions also generally develop at a younger age in transplant recipients and are more likely to occur in multiple sites.[29]

The most important risk factor for the development of non-melanoma skin cancer in renal transplant recipients is prior exposure to ultraviolet radiation.[33] In addition, the development of squamous cell carcinoma is usually associated with premalignant keratoses, Bowen's disease (squamous cell carcinoma in situ), and/or keratoacanthomas.[27] A predictive index has been developed that could be used to enable targeted screening for non-melanoma skin cancer in renal transplant recipients.[33] Predictive factors used in the index include age, outdoor ultraviolet radiation exposure, living in a hot climate, pretransplantation non-melanoma skin cancer, sunburn during childhood, and skin type.[33]

Melanoma
The risk of developing melanoma is 3.6 times greater in renal transplant recipients than in the general population.[34] An analysis of the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House showed that the risk of the development of melanoma in renal transplant recipients is positively associated with increasing age at transplantation and with the use of depleting anti-lymphocyte antibodies. By contrast, female sex, non-Caucasian race, and increasing time since transplantation were found to be inversely associated with risk of melanoma development.[34] Although renal transplant recipients are at increased risk of melanoma, some studies have found that the outcomes of melanoma in transplant recipients are no different to those in the general population.[35,36] Another study, however, reported that outcomes may be worse in transplant recipients than in the general population, as transplant recipients are more likely to have more advanced malignant melanoma at the time of diagnosis.[28]

Kaposi's Sarcoma
The incidence of Kaposi's sarcoma is much higher in renal transplant recipients than in the general population.[16] Kaposi's sarcoma is three times more common in male renal transplant recipients than in female renal transplant recipients.[37] Kaposi's sarcoma is caused by human herpesvirus 8, as will be discussed. Most cases of post-transplantation Kaposi's sarcoma occur in individuals of Mediterranean, Jewish, Arabic, Caribbean, or African descent, a finding that probably corresponds with the geographic distribution of human herpesvirus 8.[37] The choice of immunosuppressive therapy can also affect the risk of post-transplantation Kaposi's sarcoma: calcineurin inhibitors are associated with a higher risk of Kaposi's sarcoma development than are other immunosuppressive therapies.[38]

Classically, Kaposi's sarcoma presents as angiomatous lesions predominantly affecting the legs and causing lymphedema. Lesions can also occur on mucosal surfaces, lungs, gastrointestinal tract and lymphoid tissue.[38] Kaposi's sarcoma is often limited to the skin in transplant recipients, but visceral involvement—which is associated with a worse prognosis—occurs in 10% of patients.[38] The incidence of visceral involvement is lower in kidney transplant recipients than in heart or liver transplant recipients, probably because immunosuppression regimes involving calcineurin inhibitors are less intensive in renal transplantation.[38] A 2009 multi-center French study in a large cohort of renal transplant recipients found that the presence of pre-existing or acquired human herpesvirus 8 infection had no effect on patient and graft survival, which suggests that patients who are seropositive for human herpesvirus 8 should not automatically be excluded from transplantation.[39]

Lymphoproliferative Disorders
Post-transplantation lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases characterized by abnormal lymphoid proliferation occurring after organ transplantation.[40] Although PTLD usually presents as host-derived B-cell neoplasia, T-cell and donor-derived lymphomas have also been described.[40] PTLD is more common among transplant recipients than B-cell and T-cell lymphoproliferative disorders are in the general population and in patients on the waiting list for transplantation.[18] A study that analyzed United States Renal Data System data from 66,159 adult Medicare-covered kidney transplant recipients found that malignant lymphoid proliferations developed in 1,169 patients (1.8%) over an average follow-up duration of 10 years.[41] Among these patients, 70% were diagnosed with non-Hodgkin lymphoma, 14% with multiple myeloma, 11% with lymphoid leukemia, and 5% with Hodgkin lymphoma.[41] In pediatric renal transplant recipients, the reported incidence of PTLD approaches 5% at 10 years after transplantation.[42]

Although the average time to development of PTLD is 32 months after transplantation,[41] the incidence of lymphoma development is highest during the first year after transplantation, when the risk of primary viral infection is highest and the level of immunosuppression is greatest.[41] Notably, non-Hodgkin lymphoma has a more aggressive clinical course in renal transplant recipients than in the general population, with the involvement of extranodal areas and poorer outcome.[41]

Other Cancers
Merkel's Cell Carcinoma. Merkel's cell carcinoma, an aggressive neuroendocrine skin cancer, has also been described in solid-organ transplant recipients.[43,44] This cancer predominantly affects the head, neck and upper extremities, and has a more aggressive outcome in transplant recipients than in the general population. The mean time of occurrence of Merkel's cell carcinoma after transplantation has been reported to be approximately 7 years and mean survival after diagnosis is 18 months (range 0-135 months).[43,44]

Squamous Cell Carcinoma of the Eye. The incidence of squamous cell carcinoma of the eye has also been described to be 20-fold higher in renal transplant recipients than in the general population.[45] The incidence of squamous cell carcinoma of the eye is also increased in individuals with HIV infection, which suggests that this cancer type has an origin related to immune deficiency. This malignancy has also, however, been found to be associated with sun exposure.[45]

Cancers Involving the Anogenital Region. The incidence of cancers involving the anogenital region have been reported to be 100-fold higher among renal transplant recipients than in the general population.[17,46,47] The distribution of such cancer involves multiples sites, including the anus, perianal skin, and external genitalia of both sexes, and clinically this cancer manifests as maculopapular lesions.[17,46,47]

Lung Cancer. The incidence of lung cancer is higher in heart or lung transplant recipients who smoke than in nonsmoking heart or lung transplant recipients; prophylactic globulins used for induction therapy have also been associated with lung cancer in solid-organ transplant recipients.[48-50]
Pathogenesis

Malignancies after solid-organ transplantation can develop directly, through the transmission of neoplastic cells from the donor to the recipient, or through de novo occurrence in the recipient.[28] Retrospective studies of organ transplant recipients have reported that the risk of a donor organ with undetected cancer being transplanted into a recipient is about 1.3%, the risk of development of de novo neoplasia is 0.2%, and the risk of cancer developing in recipients who receive a kidney from donor with known or incidentally discovered cancer is 45%.[51,52]

A number of factors seem to be associated with the development of de novo neoplasia in transplant recipients: impairment of immune surveillance through the use of immunosuppressive drugs after transplantation; carcinogenic factors such as sun exposure; and host factors such as a genetic predisposition to cancer, the presence of particular viral infections, and pretransplantation dialysis (Figure 1).[28,53]
Immunosuppressive Therapy
The association of immunosuppressive therapy with an increased risk of cancer is well known; the incidence of cancer is higher in transplant recipients than in the general population or in patients in the waiting list.[18]

Intensity of Immunosuppressive Therapy. Some indirect evidence supports the idea that the intensity of immunosuppression after transplantation affects the risk of the development of a post-transplantation malignancy.[53-55] Firstly, heart transplant recipients (who usually receive more intense immunosuppression than renal transplant recipients) have a higher risk of malignancy after transplantation than do renal transplant recipients.[53] Secondly, the risk of PTLD is highest during the first year after transplantation, a time when the degree of immunosuppression is highest.[10,56] Thirdly, a correlation has been found between increasing ciclosporin dose and the incidence of secondary cancers.[57] Fourthly, a trial involving 231 patients randomized to receive ciclosporin doses adjusted to yield trough blood concentrations within the range 75-125 ng/ml (low-dose group) or trough blood concentrations within the range 150-225 ng/ml (normal-dose group) showed that low-dose ciclosporin was associated with a reduced incidence of cancer (19.8% versus 32.2%).[57] The use of quadruple immunosuppressive therapy (ciclosporin A, azathioprine, prednisone and antilymphocyte globulin) has also been found to be associated with a higher incidence of non-Hodgkin lymphoma than the use of triple immunosuppressive therapy (ciclosporin A, azathioprine and prednisone).[58] A correlation has also been found between CD4 lymphopenia and an increased incidence of skin cancer among kidney transplant recipients.[59 Finally, the duration of immunosuppression has been shown to be associated with a gradual and cumulative increase in the risk of neoplasia in renal transplant recipients in the long term.[33]

Choice of Drugs. The use of anti-T-cell therapy (muromonab-CD3 or antilymphocyte serum), but not anti-IL-2 receptor antibodies, has been shown predispose solid-organ transplant recipients to Epstein-Barr-virus-associated PTLD.[56] Conflicting data surround the effect of other commonly used immunosuppressive drugs on the risk of PTLD.[40] A paper published in 2007 reported that the use of thymoglobulin was associated with a significantly increased risk of PTLD (P = 0.0025), but that alemtuzumab, basiliximab or daclizumab were not associated with an increased risk of PTLD.[60]

Interestingly, the immunosuppressive effect may not be the only way in which immunosuppressant drugs confer an increased risk of malignancy. Both ciclosporin and tacrolimus have been shown to increase the levels of transforming growth factor β (TGF-β in animal models, which might lead to the development of morphological changes in non-transformed cells and tumor growth in immunodeficient animal models.[61,62] Azathioprine exposure has also been associated with an increased risk of skin cancer.[63] Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is suggested to have anti-neoplastic effects. Laboratory and animal model experiments have shown that sirolimus is able to suppress tumor growth via the inhibition of p70 S6 kinase, IL-10, cyclins, and vascular endothelial growth factors A and C.[64,65] Some clinical evidence also suggests that the incidence of post-transplantation malignancy is lower in patients receiving sirolimus than in patients receiving other immunosuppressive therapies.[14,66-70] In addition, the use of sirolimus in place of ciclosporin has been associated with complete regression of Kaposi's sarcoma in renal transplant recipients.[71,72] A large retrospective study that analyzed data from 33,249 deceased-donor primary solitary renal transplant recipients included in the Organ Procurement and Transplantation Network database found that the use of sirolimus or everolimus was associated with a reduction in the risk of post-transplantation malignancy development (relative risk 0.39, 95% CI 0.24-0.64; P = 0.0002).[73]

Exposure to Carcinogenic Factors
Exposure to carcinogenic factors is one of the most important factors in the development of neoplastic disease after solid-organ transplantation. The most-studied issue in transplant recipients is the relationship that shows that sun exposure, both before and after transplantation, is associated with an increased risk of skin cancer.[33,74,75]

Host Factors
The genetic background of the host is clearly a very important factor in the development of post-transplantation malignancy, and although outside the scope of this Review it is of utmost importance in the clinical setting.[16] Chronic pretransplantation dialysis treatment might also lead to an increased risk of cancer (particularly in the kidney, urinary tract and endocrine organs).[76] Another important host factor that is more specifically related to the issue of transplantation is the co-existence of viral infections. Several viruses have been shown to be associated with the development of different neoplastic disorders after transplantation.

Epstein-Barr Virus. Epstein-Barr virus is a gamma herpesvirus that is distributed worldwide. Antibodies against Epstein-Barr virus are found in around 90-95% of the world's population.[77] After the primary infection, which is usually subclinical, the Epstein-Barr virus remains dormant in the patient for life, most of the time without any symptoms. Epstein-Barr virus has, however, been linked to Hodgkin and non-Hodgkin lymphomas and to nasopharyngeal carcinomas.[78]

Most cases of PTLD are associated with Epstein-Barr virus infection. Epstein-Barr virus infection can lead to cell transformation that, in the setting of chronic immunosuppression, allows tumor growth.[78] Latent membrane protein-1 (LMP-1) of the Epstein-Barr virus has a central role in the pathogenesis of Epstein-Barr-virus-associated PTLD as it engages the signaling proteins from the tumor-necrosis-factor-receptor-associated factors (TRAFs) that lead to cell growth and transformation.[79-82]

As previously mentioned, some immunosuppressive regimens do seem to be associated with an increased risk of PTLD, although controversy still exists in this area. The use of muromonab-CD3 or antithymocyte globulin seems to be associated with an increased risk of PTLD mainly during the first year after transplantation, whereas the use of mycophenolate mofetil seems to be associated with a reduced incidence and later onset of PTLD.[56,83,84] Considering calcineurin inhibitors, the use of ciclosporin (with or without azathioprine or steroids) is not associated with an increased risk of malignancy in transplant recipients compared with azathioprine or steroids alone, whereas tacrolimus is commonly associated with an increased risk of malignancy compared with ciclosporin.[38,56,83-86] Finally, mTOR inhibitors might protect against the development of PTLD through the inhibition of proliferation signals: everolimus and sirolimus have shown a capacity to inhibit growth of PTLD cell lines in in vivo and in vitro models, respectively.[73-75] Although some case reports suggest that conversion to mTOR-based immunosuppressive regimens might be useful in the treatment of PTLD,[38,87-99] robust data are still lacking.

Human Herpesvirus 8. Human herpesvirus 8 is a gamma herpesvirus that has an important role in cellular proliferation and the development of malignancies. Kaposi's sarcoma is the most common neoplastic disorder associated with human herpesvirus 8, but other diseases, including primary effusion lymphoma and Castleman disease, have also been associated with human herpesvirus 8 infection.[90,91]

Human herpesvirus 8 can infect a number of different cells types including B cells, endothelial cells, macrophages, and epithelial cells.[90] Similar to other herpesviruses, human herpesvirus 8 shows a latent and lytic phase, and the transition from the latent to the lytic phase can be triggered by some cytokines and growth factors.[92] During the lytic phase, the virus produces structural and replicative gene products that lead to the production of virions.[91-94] Human herpesvirus 8 can also modulate the host immune response through a number of mechanisms including directing inflammatory cell recruitment away from a T-helper-1-type towards a T-helper-2-type response (which enables evasion from the cytotoxic immune response) and through impairment of antigen presentation and impairment of T-cell activation.[95-100] The virus can also lead to carcinogenesis by preventing apoptosis.[101,102] The presence of several oncogenes in the human herpesvirus 8 genome explains the capacity of the virus to induce tumors: the oncogenes can interfere with cell-cycle regulation and the control of apoptosis.[101-105]

A study performed in Saudi Arabia found that the proportion of patients with antibodies against human herpesvirus 8 was higher among patients who developed Kaposi's sarcoma after renal transplantation than among those who did not.[106] In addition, the incidence of Kaposi's sarcoma is higher among patients with evidence of human herpesvirus 8 infection at the time of transplantation than among patients without infection (15-28% versus <1%).[107-109] Considering these findings, screening for human herpesvirus 8 during the pre-transplantation work-up might be useful. As previously mentioned, however, seropositivity for human herpesvirus 8 is not always associated with an increased risk of developing Kaposi's sarcoma.[39] As both human herpesvirus 8 and any tumor cells derived from the donor can be transmitted from the donor to the recipient,[110,111] it may be useful to screen donors for human herpesvirus 8, at least in regions with a high prevalence of infection. The importance of the T-cell response is underscored in the setting of post-transplantation Kaposi's sarcoma: complete remission of disease can be achieved by tapering of immunosuppression or switching from calcineurin inhibitors to sirolimus, which can lead to restoration of specific human herpesvirus 8 T-cell responses.[112]
Summary of Recommendations
The approach to dealing with malignancies in the setting of solid-organ transplantation should start with preventive measures, such as the avoidance of excessive immunosuppression, the avoidance of repeated exposure to depleting anti-lymphocyte antibodies, the screening of donors and recipients for cancer, and the avoidance of carcinogenic factors such as high sun exposure.

Once detected, a malignancy should be managed with the specific therapies for the particular tumor type and with strategies such as immunosuppression reduction, immunosuppression withdrawal or conversion to alternative immunosuppressive regimens based on mTOR inhibition. In patients diagnosed with lymphoma, skin cancer or Kaposi's sarcoma, reducing the doses of calcineurin inhibitors is a good first approach to treatment.[131]

In renal transplant recipients with Kaposi's sarcoma, the substitution of calcineurin inhibitors for mTOR inhibitors (along with the reduction or discontinuation of the immunosuppressive regimen) can lead to complete regression of disease, particularly in patients with early, small, and low-grade lesions.[71,132,133]

Regression of PTLD has been described in renal transplant recipients who switched from calcineurin inhibitors to mTOR inhibitors, which suggests a potential role for this immunosuppressive drug in the management of PTLD.[41] Some anecdotal reports have documented regression of other solid-organ post-transplantation malignancies (including colon, lung, breast, stomach, and larynx cancer) after conversion to mTOR inhibitors, but such reports lack follow-up data.[134]

If a transplant recipient receiving treatment with azathioprine develops recurrent skin cancer, the discontinuation of azathioprine and conversion to mTOR inhibitors should be considered.[29] Two prospective trials in Europe and Australia are studying the potential benefits of conversion from calcineurin inhibitors to mTOR inhibitors on the recurrence of skin cancer in transplant recipients.

Although growing evidence seems to indicate that mTOR inhibitors have beneficial effects in terms of cancer regression and patient survival in the early stages of post-transplantation malignancies,[135] long-term prospective clinical trials are needed.

Malignancy is a common cause of death after renal transplantation. Clear associations have been found linking many of the immunosuppressive drugs in current use with cancer after transplantation. Research in this field is mainly focused on the development of strategies that aim to prevent or treat tumor development. In this regard, screening patients for cancer while they are on the transplantation waiting list and after they have undergone transplantation is very important. Minimizing doses of immunosuppressive drugs that are potential risk factors for cancer development is also an important prevention strategy in transplant recipients, and interest is growing in the potential antioncogenic properties and inherent immunosuppressive characteristics of mTOR inhibitors.